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Article Dans Une Revue Nature Cell Biology Année : 2022

The HASTER lncRNA promoter is a cis-acting transcriptional stabilizer of HNF1A

Anthony Beucher
Irene Miguel-Escalada
Diego Balboa
Matías de Vas
  • Fonction : Auteur
Miguel Angel Maestro
  • Fonction : Auteur
Javier Garcia-Hurtado
  • Fonction : Auteur
Aina Bernal
Roser Gonzalez-Franco
  • Fonction : Auteur
Pierfrancesco Vargiu
  • Fonction : Auteur
Holger Heyn
Sagrario Ortega
  • Fonction : Auteur
Jorge Ferrer

Résumé

Abstract The biological purpose of long non-coding RNAs (lncRNAs) is poorly understood. Haploinsufficient mutations in HNF1A homeobox A ( HNF1A ), encoding a homeodomain transcription factor, cause diabetes mellitus. Here, we examine HASTER , the promoter of an lncRNA antisense to HNF1A . Using mouse and human models, we show that HASTER maintains cell-specific physiological HNF1A concentrations through positive and negative feedback loops. Pancreatic β cells from Haster mutant mice consequently showed variegated HNF1A silencing or overexpression, resulting in hyperglycaemia. HASTER -dependent negative feedback was essential to prevent HNF1A binding to inappropriate genomic regions. We demonstrate that the HASTER promoter DNA, rather than the lncRNA, modulates HNF1A promoter–enhancer interactions in cis and thereby regulates HNF1A transcription. Our studies expose a cis -regulatory element that is unlike classic enhancers or silencers, it stabilizes the transcription of its target gene and ensures the fidelity of a cell-specific transcription factor program. They also show that disruption of a mammalian lncRNA promoter can cause diabetes mellitus.

Dates et versions

hal-03854773 , version 1 (16-11-2022)

Identifiants

Citer

Anthony Beucher, Irene Miguel-Escalada, Diego Balboa, Matías de Vas, Miguel Angel Maestro, et al.. The HASTER lncRNA promoter is a cis-acting transcriptional stabilizer of HNF1A. Nature Cell Biology, 2022, 24 (10), pp.1528-1540. ⟨10.1038/s41556-022-00996-8⟩. ⟨hal-03854773⟩
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